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Mechanisms of Action of Fu Fang Gang Liu Liquid in Treating Condyloma Acuminatum by Network Pharmacology and Experimental Validation

ABSTRACT: Condyloma acuminatum is a sexually transmitted disease characterized by the anomalous proliferation of keratinocytes caused by human papillomavirus (HPV) infection. Fu Fang Gang Liu liquid (FFGL) is an effective external prescription to treat condyloma acuminatum, but its potential molecular mechanism is still unclear. This study aimed to identify the major active ingredients and prospective targets of FFGL by using network pharmacology, molecular docking, and transcriptomics, and validating it experimentally. Network pharmacology analysis found that FFGL contains a total of 78 active compounds, from which 610 compound-related targets were screened. Among them, 59 compound-related targets overlapped with CA targets and were considered as targets with potential therapeutic effects. Protein-protein network analysis showed that AKT serine/threonine kinase 1 was the potential therapeutic target. To further confirm this result we performed RNA-seq assays on HPV18+ cells after FFGL intervention, and conducted enrichment analyses on the screened differentially expressed genes. Enrichment analyses results indicated that the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway may be a key pathway for FFGL to function. Further in vitro experiments revealed that FFGL significantly inhibited the activity of HPV18+ cells and reduced PI3K and Akt protein levels. Rescue experiment indicated that the reduction in cell viability caused by FFGL was partially restored after the use of activators of the PI3K/Akt pathway. We further explored the active components of FFCL for the treatment of condyloma acuminatum and screened two active compounds, periplogenin and periplocymarin. Molecular docking showed that these two compounds have good binding activity to AKT1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223380 | GEO | 2023/04/26

REPOSITORIES: GEO

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Project description:Hyperactivation of the PI3K/AKT pathway is observed in most NSCLCs, promoting proliferation, migration and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of the positive regulator phosphatydil-inositol-3â phosphate kinase (PIK3CA) and/or mutations of AKT1 itself. However, whereas the effects of AKT activation on mRNAs and proteins in the cell are fairly clear, the role of miRNAs as downstream targets of activated PI3K/AKT signalling is still poorly defined so far. To identify miRNAs that are targets of constitutive signalling of PI3K/AKT in lung cancer cells, we performed miRNA profiling of human lung epithelial cells expressing active mutant AKT1 (E17K), active mutant PI3KCA (E545K) or that are silenced for PTEN. We identified 28 differentially expressed miRNAs (8 up-regulated, 20 down-regulated) that were common to BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN cells. Among the 8 up-regulated miRNAs that were common to all the alterations, the miRNA most consistently up-regulated by activation of the PI3K/AKT pathway in BEAS-2B cells was miR-196a. The results reported here demonstrate that miR-196a acts as oncogene downstream the PI3K/AKT pathway, mediating the proliferative, pro-migratory and tumorigenic activity of this pathway in NSCLC cells by targeting FoxO1 and p27 expression. By adoptive expression of miR-196a in BEAS-2B cells, we demonstrated that miR-196a stimulates anchorage-dependent and -independent proliferation, migration and tumorigenicity in BEAS-2B cells. On the other hand, by use of antimir-196a in NCI-H460 cells to silence the endogenous expression of miR-196a, we demonstrate that miR-196a plays a pivotal role in mediating the stimulation of proliferation, migration and tumorigenicity induced by aberrant activation of PI3K/AKT signalling. Accordingly, we found that miR-196a was significantly overexpressed in human NSCLC-derived cell lines (n=6) and primary lung cancer samples (n=28). Finally, based on predicted binding sites for miR-196a by microRNA analysis software, we found that miR-196a affects protein levels of FoxO1 and p27 in NSCLC cells.

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Mechanisms of Action of Fu Fang Gang Liu Liquid in Treating Condyloma Acuminatum by Network Pharmacology and Experimental Validation

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